Introduction
Many individuals use cyclooxygenase-1 and cyclooxygenase-2 inhibitors (COX-1 and COX-2 nonsteroidal antiinflammatory drugs [NSAIDs]) on a regular basis. This is particularly true of the elderly, who are more prone to having osteoarthritis and rheumatoid diseases. The elderly are also more likely to have had cardiac stent placements or coronary angioplasties performed and may be taking antiplatelet medications such as the thienopyridines (e.g., ticlopidine and clopidogrel) or the newer platelet antagonists, platelet glycoprotein (GP) IIb/IIIa agents (e.g., abciximab, eptifibatide, and tirofiban). All these agents alter platelet function and may increase the risk of spinal/epidural hematoma formation if spinal axis anesthesia is used without following proper precautions. All anesthesiologists should be familiar with these agents and how they work. More importantly, they should be familiar with the established guidelines set forth by the American Society of Regional Anesthesia and Pain Medicine (ASRA) and the European Society of Anesthesiology (ESA). These guidelines will help in the decision of when these agents should be stopped before surgery/anesthesia and when it is safe to remove spinal/epidural catheters so that all patients are provided the widest possible margin of safety.
Options
Neuraxial techniques for anesthesia have been gaining popularity because of the associated improvement in patient outcomes, such as morbidity and mortality, as well as those that are more patient-oriented, such as postoperative pain relief and early ambulation. It has been suggested that it is the attenuation of the hypercoagulable response and the resulting reduction in the frequency of thromboembolism that is a major component of the decreased morbidity and mortality observed after neuraxial blockade. Nevertheless, this effect remains insufficient to be the only means of thromboprophylaxis, and antiplatelet and anticoagulant medications continue to be used concomitantly in the prevention of thromboembolism. As more potent versions of these medications are introduced, concerns regarding the risk of neuraxial bleeding have become heightened and the guidelines for the selection of the most appropriate antithrombotic pharmacologic agents continues to evolve with regard to the duration of therapy and degree of anticoagulation that are both needed and safe.
In 2007 it would have appeared that we had come full circle in the use of aspirin as the primary chemoprophylactic agent for the prevention of pulmonary embolism (PE) after hip pinning, total hip replacement surgery, and total knee replacement surgery. The material presented at the Third ASRA Consensus Conference (Vancouver, British Columbia, Canada, in April 2007) suggested that a growing body of literature showed that deep venous thrombosis (DVT) was not an accurate marker for the risk of embolic disease after total joint surgery because the incidence of PE had not declined proportionately with the decrease in the incidence of DVT that had resulted from the current use of the low-molecular-weight heparin (LMWH) regimens. This claim is further highlighted by the observation that the clinical trials that assessed the efficacy of various regimens in determining the American College of Chest Physicians (ACCP) Guidelines on Antithrombotic and Thrombolytic Therapy rarely used clinical outcomes like fatal PE or symptomatic DVT as primary endpoints but instead relied on contrast venography and duplex sonography. Subsequently, an actual reduction in clinically significant events has been difficult to demonstrate despite the successful reduction of asymptomatic thromboembolic events with standard use of antithrombotic therapy. Furthermore, when LMWH is used as the primary DVT prophylactic agent, the risk that patients may develop a deep periprosthetic hematoma or other surgical bleeding is increased. If patients do develop a deep periprosthetic hematoma, there is a substantial risk that they will also develop a prosthetic infection and need additional surgery. More important, patients might require an amputation of the involved extremity. The use of aspirin in conjunction with pneumatic compression devices, on the other hand, allows one the option of providing or continuing epidural analgesia in the postoperative period. This, in turn, allows patients to ambulate with minimal discomfort in the immediate postoperative period and actively participate in physical therapy. As a result of the aforementioned protocol, the incidence of PE is the same as that seen with LMWH therapy after total joint arthroplasty. This observation has been further demonstrated by an abstract portending a multicenter study conducted by Bozic et al involving 93,840 patients undergoing total knee arthroplasty between 2003 and 2005. The results of the study revealed patients who received aspirin for thromboprophylaxis to have had a similar risk of thromboembolism compared with patients receiving LMWH and a decreased risk compared with those who received warfarin. The authors argue that the success of aspirin as thromboprophylaxis may have been a result of changing trends in patient characteristics and evolving surgical techniques. This position is further supported by the current ACCP guidelines, which state that both aspirin and LMWH can be used as thromboprophylaxis in patients undergoing major orthopedic surgery, with the benefit that aspirin does not need to be stopped during neuraxial anesthesia practices. It is worth noting, however, that one member of the ACCP guidelines panel was so opposed to aspirin-only therapy for DVT prophylaxis in the setting of total hip or knee arthroplasty that he insisted his objections be noted in the final draft of their deliberations.
In addition, an exhaustive literature survey and meta-analysis on spinal hematomas done by Kreppel and colleagues showed that only 10% of all spinal hematomas were associated with the use of a spinal anesthetic procedure, and that 60% of these epidural hematomas were either associated with the presence of a coagulopathy or an anticoagulant had been administered to the patient. More important, none of these hematomas occurred in the presence of aspirin or NSAID therapy alone. It would therefore appear that the timing of single-shot or catheter techniques in relation to the dosing of NSAIDs or aspirin does not increase the risk of spinal hematomas.
What is the evidence, however, that aspirin chemoprophylaxis reduces the risks of thromboembolic disease to an acceptable level after joint replacement surgery? A prospective study by Lotke and Lonner used aspirin chemoprophylaxis, early ambulation, an increased use of regional anesthesia, and intermittent pneumatic compression to prevent fatal PE in 3473 consecutive patients undergoing total knee arthroplasty. Again, the authors used a reduction in the incidence of fatal PE, not DVT, to determine the effectiveness of their study protocol and compared their results with those of other studies in which more conventional chemoprophylactic agents, such as warfarin, fondaparinux, or LMWH, were used after total knee arthroplasty. The study period ran for a minimum of 6 weeks after each joint replacement. Lotke and Lonner recorded a total of nine deaths during their study: two from PE, five from cardiac events, one from stroke, one from fat embolism; three cardiac-related events also occurred for which PE could not be ruled out as the primary cause of death. Therefore the best- and worst-case scenarios for PE were 0.06% and 0.14%, respectively. Thirteen patients required reoperation to evacuate deep wound hematomas (0.4%). With regard to the incidence of fatal PE, the results of this study compare quite favorably with other studies in which more conventional chemoprophylactic agents were used to prevent PE in patients having total knee replacement. However, the incidence of fatal PE was found to be approximately 0.1% in the other studies, irrespective of the chemoprophylactic used. Finally, the incidence of adverse postoperative bleeding events in the Lotke and Lonner study was only 0.3%. This incidence is substantially lower than the rate of 2% to 5% reported in the literature with the more conventional chemoprophylactic regimens.
Evidence
Cyclooxygenase-1 Nonsteroidal Antiinflammatory Drugs
Aspirin causes inhibition of platelet function through inhibition of platelet cyclooxygenase, an enzyme that is instrumental in the biosynthesis of thromboxane A 2 from arachidonic acid. Thromboxane A 2 is necessary for the formation of thromboxane, a prostaglandin that is a potent stimulator of platelet aggregation and adhesion. Because the reaction between aspirin and platelet membrane cyclooxygenase is irreversible, inhibition of platelet function lasts for the life of the platelet (7 to 10 days).
The remaining COX-1 NSAIDs such as naproxen, ketorolac, diclofenac, piroxicam, ibuprofen, and others also act as prostaglandin synthesis inhibitors. All of them cause reversible competitive platelet inhibition, and platelet function usually returns to normal within 1 to 3 days after stopping the drug.
Horlocker and colleagues and Urmey and Rowlingson all believe that there is a minimal risk of spinal hematoma formation when preoperative antiplatelet therapy has been administered with either aspirin or another COX-1 NSAID. These authorities believe that it is not necessary to stop these agents before surgery or to avoid spinal or epidural anesthesia in patients who have been using these medications in the preoperative period. Furthermore, they believe it is safe to remove epidural catheters from patients who have been administered aspirin or NSAIDs in the postoperative period.
Tryba published an extensive review on spinal hematomas associated with regional anesthesia. Thirteen cases of hematoma were identified from the review of approximately 850,000 epidural anesthetics. Seven cases of spinal hematoma were identified from 650,000 spinal anesthetics. Statistical analysis of these data resulted in an estimated incidence of spinal hematoma of 1 : 150,000 for epidural anesthesia and an incidence of 1 : 220,000 for spinal blocks. These estimates represent the baseline risk of spinal hematoma formation with neuraxial anesthesia in the absence of antiplatelet agents.
Horlocker and colleagues retrospectively reviewed 805 charts of patients who were receiving NSAIDs and who also were administered a spinal axis anesthetic. None of the patients developed a spinal hematoma in the postoperative period. In a more recent prospective study, Horlocker and colleagues studied 924 patients who received 1000 spinal or epidural anesthetics. Of these patients, 386 (39%) were taking aspirin ( n = 193) and the remaining 193 patients were taking another COX-1 NSAID. Moreover, 32 patients in this later group were taking more than one NSAID in the preoperative period. Blood was noted during needle or catheter placement (minor hemorrhagic complications) in 223 of the patients (22%), including 73 who had frank blood in either their needle or catheter. None of the patients developed a spinal hematoma in the postoperative period. The authors concluded that preoperative antiplatelet therapy was not a significant risk factor for the development of neurologic dysfunction from spinal hematoma in patients who undergo spinal or epidural anesthesia while receiving these medications.
In another study by Horlocker and colleagues that involved 1035 patients who received 1214 epidural steroid injections, 383 of the 1035 patients (32%) were concurrently taking an NSAID. More specifically, 158 of these 383 patients were consuming aspirin and 104 of the 158 were using low-dose aspirin (325 mg/day or less). The authors conclude that epidural steroid injection is safe in patients receiving either aspirin or NSAIDs. Table 49-1 shows the combined results of the three Horlocker studies.
| Date of Study | Type of Study | Number of Epidurals/Spinals | Number Taking NSAIDs | Number Taking Aspirin | Results |
|---|---|---|---|---|---|
| 1990 | Retrospective | 924 | 301 | N/A | No hematoma formations |
| 1995 | Prospective | 1000 | 386 | 193 | No hematoma formations |
| 2002 | Prospective | 1214 | 383 | 158 | No hematoma formations |
* Presents the results of three studies by Horlocker and colleagues that demonstrate no epidural hematoma formations in 3138 patients who received either a spinal or an epidural needle placement and who were also receiving aspirin therapy or another NSAID.
Vandermeulen and colleagues, in their review of the literature from 1906 to 1993, were able to find only three cases in which an NSAID was implicated in the formation of a postspinal/postepidural hematoma. One of the cases involved indomethacin; in the two other cases aspirin was implicated. One of these later two cases also involved the concurrent use of heparin. Two of the patients had epidural anesthesia, and the third had a spinal anesthetic. The authors conclude that the incidence of spinal hematoma after the placement of either spinal or epidural blockade in patients taking aspirin or other NSAIDs was very low. However, Vandermeulen was also an author on the German Society of Anesthesiology and Intensive Care Medicine consensus statement that suggests that a risk of hematoma is present when aspirin and NSAIDs are not stopped several days before the placement of a spinal or an epidural block.
The evidence for a risk of hematoma formation if aspirin and other COX-1 NSAIDs are not stopped several days before the placement of spinal or epidural blockade is quite sparse and is limited to single-incident case reports. A report by Litz and colleagues implicates the perioperative administration of ibuprofen as the offending agent that led to the formation of a hematoma after epidural catheter removal on the second postoperative day in a patient who had undergone a total knee replacement. However, the patient was also receiving LMWH.
The most alarming report is by Gerancher and colleagues. Their patient had not undergone anticoagulation and had only received a single dose of ketorolac during surgery (30 mg intravenously) and then three doses in the postoperative period (15 mg intramuscularly every 6 hours). The patient’s lumbar hematoma developed during the afternoon of the first postoperative day, and its presence was confirmed by magnetic resonance imaging (MRI). Even more alarming was the fact that it occurred as the result of a lumbar puncture with a small-gauge spinal needle. She had required three needle passes for her block to be placed. The first two were performed with a 27-gauge Quincke needle, and bone was encountered each time. The final pass was undertaken with a 25-gauge Quincke needle. No blood was aspirated or detected during any of the needle placements. Fortunately, the woman made a full recovery from her paraparesis without surgical decompression. Moreover, the concurrent use of ketorolac and LMWH has been implicated in three reports of spinal/epidural hematomas in conjunction with an axis anesthesia. Two of these hematomas occurred immediately after the removal of an epidural catheter; therefore Litz and colleagues warn that epidural catheter removal may be just as risky as catheter placement in regard to epidural hematoma formation in patients receiving anticoagulation or antiplatelet therapy.
A 1995 case report by Heye presents a patient who was taking 250 mg/day aspirin and who developed an epidural hematoma after spinal trauma. Heye suggested that, although aspirin did not cause the bleeding, it did have a major impact on the extent of the epidural bleeding. Finally, a more recent case report by Hyderally describes a patient with ankylosing spondylitis who was undergoing total hip replacement and who was started on aspirin for postoperative thromboprophylaxis. This patient subsequently developed a thoracic epidural hematoma 36 hours postoperatively. More important, this thoracic-level epidural hematoma extended from T5 to T10, which was quite distant from the lumbar epidural catheter tip and was confirmed by an MRI to lie at L2/L3. Hyderally concluded that the hematoma was not caused by the lumbar epidural catheter placement but that it occurred spontaneously, possibly as the result of concurrent aspirin therapy and the patient’s primary disease of ankylosing spondylitis.
The scarcity of case reports related to neuraxial techniques and spinal hematoma in patients receiving antiplatelet medications is itself notable given the prevalence of NSAID use in the general American population, particularly in those with chronic pain–related illnesses. Thus, despite the aforementioned rare events, the ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation has twice concluded that use of NSAIDs alone does not significantly increase the risk of developing spinal hematomas. Combination therapy with unfractionated heparin, LMWH, or oral anticoagulants has, however, been shown to increase the frequency of hemorrhagic complications.
Areas of Uncertainty about Continuing Cyclooxygenase-1 Nonsteroidal Antiinflammatory Drugs before the Placement of an Axis Anesthetic
Although Urmey and Rowlingson believe that there is a minimal risk of spinal hematoma formation when preoperative antiplatelet therapy has been administered with either aspirin or another COX-1 NSAID, they questioned the conclusions reached by the Horlocker study because it was their belief that the study lacked adequate statistical power to conclude that there was no increased risk of spinal/epidural hematoma formation in patients taking a COX-1 NSAID. This may be particularly true for aspirin administration before the placement of an axis anesthetic. They pointed out that, although no hematomas were detected in the study, fewer than 500 patients received both a spinal axis anesthetic and either aspirin or a COX-1 NSAID. Using Tryba’s estimated incidence of spinal hematoma formation of 1 : 150,000 to 1 : 220,000, one would need a study involving almost 200,000 patients to achieve adequate power, and then there would only be an 80% probability of detecting a tenfold increase in the frequency of hematomas in patients receiving both a neuraxial block and antiplatelet therapy. Moreover, none of the patients in the Horlocker study had received either the thienopyridines (ticlopidine and clopidogrel) or the newer platelet antagonists, platelet GP IIb/IIIa agents such as abciximab, eptifibatide, and tirofiban, in the preoperative period. Finally, the most recent Horlocker study probably also lacks the statistical power to reach the conclusion that epidural steroid injections are safe in patients receiving aspirin and other COX-1 NSAIDs. Horlocker and colleagues acknowledge that the rarity of spinal hematomas makes it impossible to make definitive conclusions on the safety of epidural steroid injection in patients who are also receiving NSAID therapy.
Another area of controversy is the use of bleeding time for determining whether it is safe to place a spinal or an epidural anesthetic in a patient who has been taking aspirin in the preoperative period. Hindman and Koka do not believe that bleeding time is a reliable indicator of platelet function. Although the bleeding time may quickly normalize after aspirin ingestion, platelet function as measured by platelet response to adenosine diphosphate (ADP) or epinephrine may take up to a week to return to normal. Measurement of Ivy bleeding time before the placement of a spinal or an epidural anesthetic is not indicated and is of little value because there is no evidence to suggest that it can predict hemostatic compromise.
Cyclooxygenase-2 Nonsteroidal Antiinflammatory Drugs
The COX-2 specific inhibitors (COX-2 NSAIDs) are essentially devoid of platelet-altering activity. The COX-2 inhibitor valdecoxib (Bextra) is 28,000-fold more selective against COX-2 than COX-1. In early clinical trials valdecoxib did not affect platelet function. The same is true for the older COX-2 agents celecoxib (Celebrex) and rofecoxib (Vioxx). However, the aforementioned information is now a moot point because celecoxib is the only remaining COX-2 inhibitor on the market today in North America.
Antiplatelet Drugs
Thienopyridines (Ticlopidine, Clopidogrel, and Prasugrel) Inhibit Platelet Function
Ticlopidine (Ticlid) is a long-lasting inhibitor of both primary and secondary phases of platelet aggregation induced by ADP, collagen, thrombin, arachidonic acid, prostaglandin endoperoxidase, and thromboxane A 2 –like substances. Ticlopidine’s effect on platelet function is irreversible, and the drug’s action lasts for the lifetime of the platelet. However, prolonged bleeding time is normalized within 2 hours after the intravenous administration of methylprednisolone (20 mg) or the transfusion of platelets. The drug is indicated for reducing the risk of thrombotic events in patients who have experienced stroke precursors and who are also intolerant to aspirin. However, the aforementioned and subsequent discussions on the drug ticlopidine are probably a moot point because Apotex, the manufacturer of ticlopidine, stopped producing the drug on August 31, 2012.
Clopidogrel (Plavix) irreversibly inhibits platelet aggregation by selectively binding to adenylate cyclase–coupled ADP receptors on the platelet surface. Furthermore, by blocking the ADP receptor, clopidogrel inhibits the binding of fibrinogen to the platelet GP IIb/IIIa receptor. Clopidogrel has almost completely replaced ticlopidine because it has a wider therapeutic index, has a reduced side effect profile, and is more efficacious than ticlopidine at accepted clinical dosing parameters. It is important to note, however, that the antiplatelet effects of clopidogrel are not consistent in all patients and that up to 30% of patients have marked variability in the extent of platelet inhibition. Furthermore, up to 15% of high-risk patients with acute coronary syndrome have further ischemic events despite adequate antiplatelet therapy with clopidogrel. The reason for this variability seems to be due to the fact that clopidogrel is a prodrug and must be metabolized before it can bind to ADP receptors and inhibit platelet aggregation. The metabolic activation of clopidogrel is catalyzed by CYP2C19, a genetically pleomorphic CYP-450 enzyme with a common single nucleotide polymorphism (SNP) that results in a truncated protein product with limited enzymatic activity. An SNP is a variation in the genetic code that occurs when a single nucleotide in the genome differs between members of the same species at the same location or between paired chromosomes within the individual. Several studies have shown this genetic variation in the CYP 450 enzyme and the resulting reduction in enzymatic activity to be associated with decreased activation of the drug, resulting in lessened antiplatelet inhibition and an increased likelihood of cardiovascular events. In addition, these observations have been supported by a genome-wide association study. Consequently, several studies are under way to assess the effect of adjustments in dosing regimens in patients with CYP2C19 variant alleles; however, it is currently unclear whether genotyping to predict response to clopidogrel is clinically useful.
Prasugrel (Effient) is the newest of the thienopyridines and has been demonstrated to inhibit platelet aggregation by a similar mechanism of irreversibly binding to ADP receptors; however, it does so to a greater extent, with more consistency, and at a more rapid pace. Currently, the only labeled indication for prasugrel in the United States is for patients undergoing percutaneous coronary intervention in the wake of acute coronary syndrome.
Ticlopidine prolongs template bleeding time. It also displays nonlinear pharmacokinetics, and its clearance decreases markedly with repeated dosing. The half-life after a single 250 mg oral dose is 12.6 hours, but with repeated dosing at 250 mg twice daily, the elimination half-life rises to 4 to 5 days. Ticlopidine has been implicated as the medication that caused a spinal hematoma in a 70-year-old woman who was having her toe amputated. Ticlopidine was administered for 10 days before surgery, but it was stopped just before the surgery. She underwent several unsuccessful attempts at spinal block placement with a 23-gauge needle in the lumbar region, and she ultimately received a general anesthetic. On the sixth postoperative day the patient developed muscle weakness in both legs. On postoperative day 8 she had cervical myelography that showed an extramedullary block below the level of T10. She underwent an emergency laminectomy, and a hematoma was evacuated from the subarachnoid space. The clot extended from T10 to L5. She remained paralyzed after the laminectomy and died the next day.
Another case report by Maier and colleagues in 2002 revealed another ticlopidine-related hemorrhagic complication; this time it was in the setting of lumbar sympathetic blockade. A 71-year-old man with progressive peripheral artery disease, taking ticlopidine for stroke prevention in the setting of carotid artery stenosis, underwent a lumbar sympathetic blockade for symptomatic relief. Unfortunately, his ticlopidine was continued during the intervention given the presumed absence of increased bleeding risks based on the patient’s history and physical examination. Two days later, a widespread skin hematoma developed, and laboratory tests revealed a 2.2-g/dL drop in hemoglobin that prompted termination of ticlopidine therapy. The patient then underwent a second lumbar sympathetic block (6 days after the first one) and subsequently developed a large retroperitoneal hematoma that was associated with severe groin pain, a drop in blood pressure and hemoglobin level, and ultimately required the patient to undergo transfusion for hemodynamic stabilization. Of possible importance is the fact that during the second block, the 25-gauge block needle was discovered to be in an intravascular position. However, usually little clinical significance is attributed to the intravascular placement of a 25-gauge needle, even in heparinized patients, despite the difficulty of compressing the deep-set vessels potentially punctured by deep plexus blocks. The case report therefore prompted the authors to question the role of ticlopidine as a direct (or contributing) factor in the development of this retroperitoneal hematoma and to raise concern regarding the risk of anesthesia-related hemorrhagic complications in patients receiving ticlopidine therapy. The authors further urged the discontinuation of irreversible platelet inhibitors 7 days before any invasive techniques, given the absence of reliable and sensitive tests to ascertain the level of adequate platelet function in these patients.
The elimination half-life of orally administered clopidogrel is only 7.7 hours after a single 75-mg dose, but the irreversible platelet inhibition persists for several days after withdrawal of the drug and diminishes in proportion to platelet renewal. Clopidogrel is 40 to 100 times more potent than ticlopidine, and bleeding times are significantly prolonged at 1 hour after the administration of a single oral loading dose of 375 mg.
Clopidogrel was implicated as one of the agents that may have led to the development of a cervical epidural hematoma in a patient who had received a cervical epidural steroid injection. He was taking several antiplatelet medications just before block placement (i.e., diclofenac, clopidogrel, and aspirin). Quadriparesis developed 30 minutes after the performance of the cervical epidural steroid injection, and he did not regain lower extremity function after his C3/T3 hematoma was surgically evacuated. There is no case report in the literature that implicates clopidogrel alone as the causative agent in the production of a postneuraxial block spinal hematoma. The aforementioned epidural case report highlights the fact that the effects of clopidogrel plus aspirin are additive and they may even be synergistic, depending on the method used to ascertain platelet function. This may explain why cardiac surgical patients who have received this drug combination appear to have excessive bleeding and why it would seem prudent to refrain from placing neuraxial blocks and deep plexus blocks in patients taking this drug combination but who have not been free of the drugs for the 7-day period suggested by the ASRA guidelines. Maier and colleagues also report another catastrophic outcome when the ASRA guidelines were not followed to the letter for a patient who was receiving clopidogrel and underwent a lumbar spinal block. In this 2002 case report, a 79 year-old woman succumbed to complications after the placement of a lumbar spinal block; at autopsy she was found to have a massive retroperitoneal hematoma. This adverse outcome may have occurred because the patient’s clopidogrel was not discontinued until just 3 days before the procedure, and the anesthesia care team relied on the fact that all of her coagulation variables had normalized, including bleeding time. It is important to remember that the antiplatelet drugs do not alter the coagulation cascade, and testing for the activated partial thromboplastin time (aPTT), prothrombin times, and international normalized ratio (INR) are of no value. Furthermore, there is no value in obtaining a bleeding time. Bleeding times are highly variable, are very operator dependent, and do not reliably indicate whether platelets are functioning at an adequate level.
Prasugrel irreversibly inhibits 50% of platelets after a single oral dose and has a maximum effect 2 hours after administration. Platelet aggregation normalizes in 7 to 9 days after termination of therapy, and the drug label recommends discontinuing the drug “at least 7 days before any surgery.” Despite the absence of any series involving performance of neuraxial blockade in the presence of prasugrel, the ESA has established guidelines along with a very strong warning for the placement of neuraxial blocks in patients receiving or who have received prasugrel. The ESA guideline reads as follows: “In view of the higher incidence of bleeding compared to clopidogrel, neuraxial anesthesia should be strongly discouraged during prasugrel treatment, unless a (prasugrel free) time interval of 7-10 days can be observed.” The ASRA has no guidelines for the placement of neuraxial blocks in patients who are receiving or have received prasugrel; however, Horlocker, the first author on all of the ASRA Anticoagulation Guidelines, authored a recent review article on regional anesthesia and antiplatelet therapy. She was in total agreement with the ESA Guidelines and suggests a 7- to 10-day prasugrel free interval before undertaking the placement of a neuraxial block or any other invasive procedure.
It is important to remember that many patients may come to the operating room or interventional suite already taking one of the aforementioned antiplatelet agents, given their use in the prevention of arterial thrombosis in multiple high-prevalence conditions such as ischemic heart disease, cerebrovascular disease, and peripheral artery disease. It is estimated that the number of patients taking antiplatelet agents requiring surgical or invasive procedures has reached 250,000 people annually, which has prompted the ACCP to set forth guidelines recommending the perioperative management of antithrombotic therapy in this setting. The guidelines seek to balance the risk of thromboembolism against those of bleeding so that adverse clinical outcomes can be minimized. As such, patients taking antiplatelet medications are stratified according to risk. In patients with a coronary stent who require surgery, the ACCP recommends deferring surgery until 6 weeks after bare-metal stent placement and until 6 months after drug-eluting stent placement instead of undertaking surgery within these time frames. If surgery cannot be delayed, however, the ACCP recommends continuing antiplatelet therapy preoperatively instead of stopping therapy 7 to 10 days before surgery. It is worth noting that aspirin can be continued around the time of surgery and the ACCP does not require stopping therapy before surgery.
Platelet Glycoprotein IIb/IIIa Antagonists
The identification of the platelet GP IIb/IIIa receptor, a fibrinogen receptor important for platelet aggregation, has led to the development of platelet receptor antagonists. Activated GP IIb/IIIa receptors become receptive to fibrinogen, and when fibrinogen binds to the GP IIb/IIIa receptors located on two different platelets, it builds the crosslinks for platelet-to-platelet aggregation. GP IIb/IIIa also mediates platelet adhesion and spreading.
Abciximab is a monoclonal antibody that binds nonspecifically to the GP IIb/IIIa receptor. The binding of abciximab to the platelet IIb/IIIa receptor is a rapid high-affinity interaction, and all the receptors are blocked within 15 minutes after the parenteral administration of a bolus dose of 0.25 mg. The biologic half-life of abciximab is approximately 12 to 24 hours, but 24 hours after administration, 50% to 60% of the platelet receptors are still blocked. Abciximab can be detected on circulating platelets for more than 15 days, which indicates platelet-to-platelet transfer. Abciximab cannot be effectively reversed with the transfusion of platelets because the new platelets are inactivated by the free-circulating monoclonal antibody or platelet-to-platelet transfer of the drug. Platelet function recovers over the course of 48 hours because of platelet turnover. Abciximab prolongs activated clotting time (ACT) by 30 to 80 seconds, and the aPTT is also prolonged. Comparative studies have shown that abciximab is superior to the other agents in preventing ischemic complications after percutaneous coronary interventions. However, its potent inhibition of platelets also renders it likely to cause increased episodes of major bleeding.
Eptifibatide is a small cyclic heptapetide. The drug sits in the binding pocket between the IIb and IIIa arms of GP IIb/IIIa and prevents the binding of fibrinogen and thrombus formation. Eptifibatide has a plasma half-life of 2.5 hours, with a rapid onset of action and a rapid reversibility of platelet inhibition. Four hours after the termination of an eptifibatide infusion, platelet aggregation recovers to approximately 70% of normal and hemostasis normalizes. The majority of the drug is eliminated by renal clearance. Eptifibatide prolongs ACT by 40 to 50 seconds, but it has no effect on prothrombin time or aPTT.
Tirofiban is a tyrosine derivative. Tirofiban occupies the binding pocket on the GP IIb/IIIa receptor and competitively inhibits platelet aggregation mediated by fibrinogen and von Willebrand factor. It is given via an intravenous infusion, and the plasma half-life is approximately 1.5 to 2.5 hours. Greater than 70% of tirofiban is cleared by biliary elimination. The remainder is eliminated by renal excretion, and the drug may be removed by hemodialysis. The ACT is prolonged by 40 to 50 seconds.
There are no known case reports of a spinal/epidural hematoma forming as the result of spinal axis blockade being performed in a patient who was simultaneously being treated with a GP IIb/IIIa antagonist. However, two studies show that patients who were using GP IIb/IIIa medications and required emergency cardiac surgery were at increased risk of having major bleeding compared with patients having elective surgery. Eleven consecutive patients who were taking abciximab and required emergency cardiac surgery after failed angioplasty or stent placement were randomly assigned to two groups. Group 1 patients ( n = 6) had taken the last dose of abciximab 12 or less hours before surgery, and group 2 patients ( n = 5) had taken it more than 12 hours before their surgery. Group 1 patients required 20 packs of platelets to control bleeding, whereas group 2 patients did not require any platelets ( p < 0.02). Group 1 patients also required more packed erythrocyte transfusions (6 versus 0; p < 0.02). The results of the Gammie study are outlined in Table 49-2 .
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